The present invention relates to a class of novel compounds, to methods and intermediates for preparing the compounds, to pharmaceutical compositions comprising the compounds, and to use of the compounds and the pharmaceutical compositions. Specifically, the present invention relates to a class of compounds having higher inhibitory activity on protein kinase G (PKG), to methods and intermediates for preparing the compounds, to pharmaceutical composition comprising the compounds, and to use of the compounds and the pharmaceutical compositions for treating pain, especially for treating chronic pain.
Pain is a result of communication between two major nervous systems, i.e., the central and peripheral nervous systems. Subjective experiences of humans are resulted from the combined effects of the two major nervous systems, which, however, are different in physiological structure and function.
The pain stimulation resulted from the impact on a particular pain receptor transmits along the primary nociceptive sensory neurons at a dorsal root ganglion (DRG, a part of the peripheral nervous system), and then transmits in the spinal cord (a part of the central nervous system), where the signal is forwarded to the second-order neurons, transmitted to the opposite side of the spinal cord, and finally transmitted to a higher center in brain, where pain is sensed.
The peripheral pain receptors having response to mechanical, heat and chemical stimulations are positioned at the nerve endings of the primary nociceptive sensory neurons. The activation of these receptors can result in acute or chronic pain. The acute pain tends to be intense and indiffusible, and generally transmits along the axon having a thin myelin sheath of a delta sensory neuron. The chronic pain tends to be dull and diffusible, and generally transmits along the unmyelinated axon of a C-type nociceptive sensory neuron.
At different stages of a pain pathway, the pain perception may be changed. For example, the pain stimulation can be eliminated when a local anesthetic is administered to a peripheral receptor. As is known to all, in the pain pathway, drugs like paperamine exhibit an inhibitory effect in the central nervous system, and non-steroidal anti-inflammatory drugs exhibit an inhibitory effect in the peripheral nervous system. Generally, the chronic pain perception in a non-primary spinal cord injury is not only related to the sensitization of the peripheral pain receptor, but also related to the alteration of the excitability of the second-order neuron. There are peripheral and central nervous systems, which adjust “primary” and “secondary” hyperalgesias, respectively. In the secondary hyperalgesia, the gene expression of the second-order neuron in the central nervous system alters, which results in the phenomenon of “central sensitization” or “spinal cord hyperalgesia”. The N-methyl-D-aspartic acid (NMDA) receptor in the spinal cord plays an important role in this process.
A spinal cord injury without the activation of the peripheral nervous system can also result in spinal cord hyperalgesia, causing central pain syndrome. Central neuropathic pain is related to the phosphorylation of cAMP response element-binding protein (CREB) transcriptional factor.
Chronic pain starts from periphery, and is caused by a neural injury (neuropathic pain) or inflammation. The pain caused by both of the causes is the major clinical problem which hinders an effective treatment. In models of humans and mammals, the constant pain after a neural injury is related to the long-term hyperexcitation (LTH) of primary sensory neurons, the axons of which are positioned at the injured ganglions. The long-term hyperexcitation occurs due to the increasing sensitization to the cell bodies and axons of pain sensory neurons at an injured site by electric stimulations. These alterations result in the release of action potential from sensory neurons at rest or without nociceptive stimulus, which causes a continuous excitation of high-order neurons in the central nervous system, spinal cord hyperalgesia and constant pain.
U.S. Pat. No. 6,476,007 relates to the mechanism of inflammatory hyperalgesia in the central nervous system, but the role of the peripheral nervous system is not considered therein. There are many significant disadvantages in drugs targeting the pain path of the central nervous system. Firstly, the neuronal circuits in the spinal cord are very complicated, and thus drugs predicted to relieve pain may have an opposite effect. Secondly, the blood-brain barrier, which separates the neurons in the central nervous system from the rest parts of the body, is generally a significant obstacle for a large number of therapeutic drugs to get to a target. Thirdly, drugs which cross the blood-brain barrier enter the entire central nervous system, causing significant toxic and side effects. Such an obstacle, however, does not exist in the peripheral nervous system. The structural characteristics of DRG show that treatment targeting a particular cluster of primary sensory neurons can be performed. Fourthly, pain can be perceived only when signals from the periphery are transmitted to the higher center in brain, and the neurons in DRG are the entrance for these signals.
Activated PKG plays a determinant role in the inhibition of pain (see WO2006/102267). After the peripheral nervous system is injured, the activity of nitric-oxide synthase (NOS) increases, which results in an improved yield of nitric oxide (NO). NO activates soluble guanylyl cyclase (sGC), and thus the level of cyclic guanosine monophosphate (cGMP) is raised, causing PKG activation in the axons of the C-type and A-s-type pain neurons. Then, activated PKG transmits reversely along the axons from the injured site to the cell bodies of neurons, mitogen activated protein kinase-erk (MAPKerk). Subsequently, activated MAPKerk is transferred into nuclei, and adjusts the expression of pain related genes which adjust the presence of LTH. As such, the inhibition of PKG can relieve pain, and reduce the level of messenger RNA (mRNA) related to nociception proteins.
Therefore, compounds which can selectively inhibit the activity of PKG in the peripheral nervous system are needed in the art. The inhibition of activated PKG can not only prevent its transmission via the peripheral nervous system, but also block its activity in cells. US patent application No. US2008/0176920 describes compounds inhibiting the activated form of PKG, and use thereof in relieving pain, especially in relieving chronic pain syndrome. In this patent application, compound 46 is described as a compound having relatively higher activity. The inventors of the present application prepared compound 46 and its analog JK-02A according to the method described in US patent application No. US2008/0176920, and tested the activity of these agents. The test result shows that this class of compounds is not good enough in water solubility, and is not high enough in PKG inhibitory activity. As such, the inventors of the present application designed a class of compounds having better water solubility and higher inhibitory activity.
